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| United States Patent |
5,637,610
|
|
Nakabayashi
, et al.
|
June 10, 1997
|
Composition containing dioxabicyclo [3.3.0] octane derivative
Abstract
A food, drink, pharmaceutical, cosmetic composition or food additive
comprising a dioxabicyclo[3.3.0]octane derivative represented by the
following general formula (I):
##STR1##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1;
and antioxidant.
| Inventors:
|
Nakabayashi; Ayako (Kyoto, JP);
Kitagawa; Yoshinori (Ibaraki, JP);
Akimoto; Kengo (Ibaraki, JP);
Sugano; Michihiro (Fukuoka, JP)
|
| Assignee:
|
Suntory Limited (Osaka, JP)
|
| Appl. No.:
|
262389 |
| Filed:
|
June 20, 1994 |
Foreign Application Priority Data
| Current U.S. Class: |
514/458; 514/469; 514/470; 514/824 |
| Intern'l Class: |
A61K 031/355; A61K 031/34 |
| Field of Search: |
514/458,469,470,824
|
References Cited
U.S. Patent Documents
| 4427694 | Jan., 1984 | Benecke et al. | 424/282.
|
| 4836987 | Jun., 1989 | Shibata et al. | 422/101.
|
| Foreign Patent Documents |
| 0 207 735 | Jun., 1986 | EP.
| |
| 0 387 000 | Mar., 1990 | EP.
| |
| 0 409 654 | Jul., 1990 | EP.
| |
| 0 488 513 | Oct., 1991 | EP.
| |
| 60-224629 | Nov., 1985 | JP.
| |
| 2-138120 | May., 1990 | JP.
| |
Other References
Chemical Abstract No. 235163x (JP-A-62 172 086) (1992).
Yamashita et al., "Sesame Seed Lignans and .gamma.-Tocopherol Act
Synergistically to Produce Vitamin E Activity in Rats," American Institute
of Nutrition, 1992, pp. 2440-2446.
Nippon Nogeikagaku Kaishi, vol. 6, No. 3, Mar. 1992, pp. 218 (3Lp13).
Nagata, et al., "Stereochemical Structures of Antioxidative
Bisepoxylignans, Sesaminol and its Isomers, Transformed from Sesamolin,"
Agric. Biol. Chem., 51(5), 1285-1289, 1987.
Osawa, et al., "Sesamolinol, a Novel Antioxidant Isolated from Sesame
Seeds," Agric. Biol. Chem, 49(11), 3351-3352, 1985.
The Merck Index, 11th Edition, 1989, p. 1343.
|
Primary Examiner: Jordan; Kimberly
Attorney, Agent or Firm: Burns, Doane, Swecker & Mathis, L.L.P.
Parent Case Text
This application is a continuation of application Ser. No. 07/897,756,
filed Jun. 12, 1992 now abandoned.
Claims
We claim:
1. A pharmaceutical composition comprising a dioxabicyclooctane derivative
represented by the following general formula (I):
##STR5##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1;
and an antioxidant, wherein the ratio of dioxabicyclooctane derivative to
antioxidant is from about 0.05 to 20.
2. A pharmaceutical composition according to claim 1, wherein the
dioxabicyclooctane derivative is sesamin, sesaminol, episesamin,
episesaminol, sesamolin,
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicycl
ooctane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclooctane or
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyc
looctane.
3. A pharmaceutical composition according to claim 1, wherein the
antioxidant is tocopherol.
4. A pharmaceutical composition according to claim 1, wherein the action of
dioxabicyclooctane derivative is lowering cholesterol value.
5. A food additive comprising a dioxabicyclooctane derivative represented
by the following general formula (I):
##STR6##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1;
and an antioxidant, wherein the ratio of dioxabicyclooctane derivative to
antioxidant is from about 0.05 to 20.
6. A food additive according to claim 5, wherein the dioxabicyclooctane
derivative is sesamin, sesaminol, episesamin, episesaminol, sesamolin,
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicycl
ooctane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclooctane or
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyc
looctane.
7. A food additives according to claim 5, wherein the antioxidant is
tocopherol.
8. A food additive according to claim 5, wherein the action of
dioxabicyclooctane derivative is lowering cholesterol value.
9. A food or drink to which a dioxabicyclooctane derivative represented by
the following general formula (I):
##STR7##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1;
and an antioxidant have been added, wherein the ratio of
dioxabicyclooctane derivative to antioxidant is from about 0.05 to 20.
10. A food or drink according to claim 9, wherein the dioxabicyclooctane
derivative is sesamin, sesaminol, episesamin, episesaminol, sesamolin,
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicycl
ooctane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclooctane or
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyc
looctane.
11. A food or drink according to claim 9, wherein the antioxidant is
tocopherol.
12. A food or drink exhibiting enhanced actions of dioxabicyclooctane
derivative prepared by adding an antioxidant to a food or drink containing
dioxabicyclo-octane derivative, wherein the ratio of dioxabicyclo-octane
derivative to antioxidant is from about 0.05 to 20, wherein the
dioxabicyclooctane derivative is represented by the formula (I):
##STR8##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1.
13. A food or drink according to claim 12, wherein the antioxidant is
tocopherol.
14. A food or drink according to claim 12, wherein the dioxabicyclooctane
derivative is sesamin, sesaminol, episesamin, episesaminol, sesamolin,
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicycl
ooctane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclooctane or
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxy-phenoxy)-3,7-dioxabicy
clooctane.
15. A method for lowering cholesterol value in a mammal comprising adding
to a food or drink a dioxabicyclooctane derivative represented by the
following general formula (I):
##STR9##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1;
and an antioxidant, wherein the ratio of dioxabicyclooctane derivative to
antioxidant is from about 0.05 to 20, and administering the food or drink
to a mammal in an amount effective for lowering the cholesterol value of
said mammal.
16. A method according to claim 15, wherein an effective amount is 1 to 100
mg/day of dioxabicyclooctane derivative and antioxidant orally
administered to an adult human.
17. A method according to claim 15, wherein an effective amount is 0.1 to
20 mg/day of dioxabicyclooctane derivative and antioxidant parenterally
administered to an adult human.
18. A method according to claim 15, wherein the dioxabicyclooctane
derivative is sesamin, sesaminol, episesamin, episesaminol, sesamolin,
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy
-4-hydroxyphenyl)-3,7-dioxabicyclooctane,
2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclooctane or
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxy-phenoxy)-3,7-dioxabicy
clooctane.
19. A method according to claim 15, wherein the antioxidant is tocopherol.
20. A pharmaceutical composition comprising a sesamin and/or an episesamin
and tocopherol so that the ratio of the sesamin and/or episesamin to the
tocopherol is from about 0.05 to 20.
21. A method for enhancing in vivo an action of a dioxabicyclooctane
derivative represented by the following general formula (I):
##STR10##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1;
comprising blending the dioxabicyclooctane derivative With an antioxidant,
wherein the ratio of dioxabicyclooctane derivative to antioxidant is from
about 0.05 to 20; and administering the mixture to a mammal in an amount
effective for enhancing in vivo the action of the dioxabicyclooctane
derivative in said mammal.
22. A method according to claim 21, wherein the dioxabicyclooctane
derivative is sesamin, sesaminol, episesamin, episesaminol, sesamolin,
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicycl
ooctane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclooctane or
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyc
looctane.
23. A method according to claim 21, wherein the antioxidant is tocopherol.
24. A method according to claim 21, wherein 1 to 100 mg/day of the
dioxabicyclooctane derivative and antioxidant mixture are orally
administered to an adult human.
25. A method according to claim 21, wherein an effective amount is 0.1 to
20 rag/day of dioxabicyclooctane derivative and antioxidant parenterally
administered to an adult human.
26. A method according to claim 21, wherein an effective amount is 1 to 100
mg/day of the dioxabicyclooctane derivative and antioxidant mixture orally
administered to an adult human.
27. A method according to claim 21, wherein an effective amount is 0.1 to
20 mg/day of dioxabicyclooctane derivative and antioxidant parenterally
administered to an adult human.
28. A method according to claim 21, wherein the action of
dioxabicyclooctane derivative is lowering cholesterol value.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a food or pharmaceutical composition
containing a dioxabicyclo[3.3.1]octane derivative and an antioxidant.
2. Description of the Related Art
U.S. Pat. No. 4,427,694 discloses that sesamin is effective for alleviating
the symptoms of alcohol intoxication and/or alcohol or tobacco withdrawal,
and Japanese Unexamined Patent Publication No. 2-138120 discloses that
sesaminol and episesaminol are effective for therapeutic or prophylactic
treatment of allergic diseases such as bronchial asthma.
Nevertheless, compounds which are safe and enhance the activities of
dioxabicyclo[3.3.0]octane derivatives are not known, and therefore, there
is a desire for a development of novel compositions providing enhanced
actions of dioxabicyclo[3.3.0]octane derivatives.
Note, the present inventors have proposed various uses of
dioxabicyclo[3.3.0]octane derivatives, including an inhibition of
.DELTA..sup.5 -desaturase (Japanese Unexamined Patent Publication No.
3-27319), an improvement of liver functions (Japanese Patent Application
No. 2-002345), a lowering of cholesterol levels (Japanese Patent
Application No. 2-002637), an inhibition of oncogenesis (Japanese Patent
Application No. 2-002818), and a prevention of sickness due to alcohol
(Japanese Patent Application No. 3-104016).
It is known that sesaminol, and 3 possible stereoisomers thereof, i.e.,
2-episesaminol, 6-episesaminol and disesaminol are antioxidant lignan-type
compounds (Agr. Biol. Chem. 51(5), 1285-1289, 1987). Sesaminol also is
known as a natural antioxidant substance (Agr. Biol. Chem 49(11) 3351-3352
(1985))
U.S. Pat. No. 4,836,987 discloses compounds having lignan backbone and
oxygen-containing sidechain on oxygen-containing ring, such as l-sesamin,
sesamolin etc. exhibit acceleration of blood clotting action and
hemostatic action.
Japanese Unexamined Patent Publication No. 60-224629 discloses an agent for
inhibiting in-vivo formation of peroxidated lipid comprising sesame
extract having antioxidant activity.
As a use of sesamin, insecticide synergest in known. Moreover, as a use of
sesamolin, synergestics of pyrethrum insecticides are known (The MERCK
INDEX 11th Edition 1989, 1343).
SUMMARY OF THE INVENTION
Accordingly, the present invention provides pharmaceutical compositions,
food and drink, as well as food additives, comprising
dioxabicyclo[3.3.0]octane derivatives and a compound which enhances the
actions of the dioxabicyclo[3.3.0]octane derivatives.
More particularly, the present invention provides a pharmaceutical
composition comprising a dioxabicyclo[3.3.0]octane derivative represented
by the formula (I):
##STR2##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1,
and an antioxidant.
The present invention further provides a food additive comprising a
dioxabicyclo[3.3.0]octane derivative represented by the following general
formula (I):
##STR3##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1,
and an antioxidant.
The present invention further provides a food or drink comprising a
dioxabicyclo[3.3.0]octane derivative represented by the following general
formula (I):
##STR4##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently represent a hydrogen atom or an alkyl group having 1 to 3
carbon atoms, or R.sup.1 and R.sup.2 and/or R.sup.4 and R.sup.5 together
form a methylene group or an ethylene group, and n, m and l are 0 or 1,
and an antioxidant.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As the dioxabicyclo[3.3.0]octane derivative, in the present invention,
sesamin, sesaminol, episesamin, episesaminol, sesamolin,
2-(3,4-methylenedioxyphenyl)-6
-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane,
2,6-bis-(3-methoxy-4-hydroxyphenyl)-3, 7-dioxabicyclo[3.3.0]octane or
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyc
lo[3.3.0]octane can be used. These derivatives can be used alone or in the
form of a mixture of two or more thereof.
The compound used in the present invention, and an extract composed mainly
of the compound of the present invention, can be obtained according to the
following procedures. First, an extract composed mainly of the compound of
the present invention can be obtained from sesame oil, by a method
comprising extracting sesame oil with an organic solvent substantially
immiscible with sesame oil and capable of extracting and dissolving the
compound of the present invention, and concentrating the extract. As the
organic solvent, there can be mentioned, for example, acetone, methylethyl
ketone, diethyl ketone, methanol and ethanol. For example, an extract
composed mainly of the compound of the present invention can be obtained
by mixing sesame oil homogeneously with an organic solvent as mentioned
above, allowing the mixture to stand at a low temperature, carrying out a
phase separation according to a customary process, and removing the
solvent from the solvent fraction by evaporation.
More specifically, sesame oil is dissolved in 2 to 10 volumes, preferably 6
to 8 volumes of acetone, and the solution is allowed to stand at
-80.degree. C. overnight. As a result, the oil component is precipitated
and the organic solvent is removed from the obtained filtrate by
distillation, whereby an extract composed mainly of the compound of the
present invention is obtained. Alternatively, sesame oil is mixed with hot
methanol or hot ethanol, the mixture is allowed to stand at room
temperature, and the solvent is removed from the solvent fraction to
obtain an extract composed mainly of the compound of the present
invention. More specifically, sesame oil is mixed with hot methanol
(higher than 50.degree. C.) or hot ethanol (higher than 50.degree. C.) in
a volume of 2 to 10 times, preferably 5 to 7 times the volume of the
sesame oil, to effect a violent extraction. The phase separation is
effected by a phase separation when standing at room temperature or a
centrifugal separation according to customary procedures, and the solvent
is removed from the solvent fraction by distillation to obtain an extract
composed mainly of the compound of the present invention. Furthermore, the
supercritical gas extraction can be utilized.
The compound of the present invention can be obtained from an extract as
mentioned above by treating the extract by a customary method such as
column chromatography, high performance liquid chromatography,
recrystallization, distillation, or liquid-liquid countercurrent
distribution chromatography. More specifically, by using a reversed phase
column (5C.sub.18) and methanol/water (60/40) as the eluent, the extract
is subjected to high performance liquid chromatography, the solvent is
removed by distillation, and the obtained crystal is recrystallized from
ethanol to obtain the compound used in the present invention, such as
sesamin, episesamin, sesaminol or episesaminol. The sesame oil used in the
present invention can be either a purified product or a crude product.
Furthermore, sesame seeds or sesame lees (defatted sesame seeds having a
residual oil content of 8 to 10%) can be used. In this case, sesame seeds
or sesame lees are pulverized if necessary, and then subjected to the
extraction according to customary procedures using any solvent, for
example, a solvent as mentioned above with respect to the extraction from
sesame oil. The extraction residue is separated, and the solvent is
removed from the extract by evaporation or the like to obtain an
extraction product.
The compound used in the present invention, for example, sesamin,
sesaminol, episesamin, episesaminol, sesamolin,
2-(3,4-methylenedioxyphenyl)-6
-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane,
2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyc
lo[3.3.0]octane, can be obtained from a sesame seed extract, a sesame lee
extract or a crude sesame oil extract according to the same procedures as
described above. Moreover, the compound used in the present invention can
be obtained from a by-product formed in the sesame oil-preparing process.
Note, sesamin obtained from Piper longum L exhibits the same effects as
those provided by sesame seeds, sesame lee and sesame oil. Moreover,
optically active isomers of the above-compounds also may be used in the
present invention.
The process for the purification of the compound used in the present
invention and the process for obtaining the extract are not limited to
those mentioned above, and the compound used in the present invention and
the extract composed mainly of the compound of the present invention are
not limited to those obtained from sesame oil, sesame lees and sesame
seeds, but as is apparent to persons with ordinary skill in the art, all
natural substances containing the compound used in the present invention
can be used. For example, there can be mentioned Acanthopanax
ghacilistylus, Asari Herba Cum Redice, Ginkgo-biloba and Piper lonqum L.
The following processes can be adopted for the synthesis of the compound of
the present invention.
For example, sesamin and episesamin can be synthesized according to the
process of Beroza et al. [J. Am. Chem. Soc., 78, 1242 (1956)]. Pinoresinol
[in the general formula (I), R.sup.1 and R.sup.4 represent H, R.sup.2 and
R.sup.5 represent CH.sub.3, and n, m and l are zero] can be synthesized
according to the process of Freundenberg et al. [Chem. Ber. 86, 1157
(1953)]. Furthermore, syringaresinol [in the general formula (I), R.sup.1
and R.sup.4 represent H, R.sup.2, R.sup.3, R.sup.5 and R.sup.6 represents
CH.sub.3, n is zero, and each of m and l is 1] can be synthesized
according to the process of Freundenberg et al [Chem. Ber., 88, 16
(1955)].
The compound used in the present invention also can be used in the form of
a glycoside. Furthermore, compounds used in the present invention can be
used alone or in combination.
As antioxidants of the present invention, there are included natural
antioxidants such as tocopherols, flavone derivatives, phyllodulcins,
kojic acid, gallic acid derivatives, catechins, fukinolic acid, gossypol,
pyrazine derivatives, sesamol, guaiacol, guaiac resin, p-cumaric acid,
nordihydroguaiaretic acid, sterols, terpenes, purine or pyrimidine bases,
carotenoides and the like, as well as synthetic antioxidants such as
butylhydroxyanisol (BHA), butylhydroxytoluene (BHT), mono-tert.-butyl
hydroquinone (TBHQ), 4-hydroxymethyl-2,6-di-tert.-butylphenol (HMBP) and
the like.
The tocopherols include .alpha.-tocopherol, .beta.-tocopherol,
.gamma.-tocopherol, .delta.-tocopherol, .epsilon.-tocopherol,
.xi.-tocopherol, .eta.-tocopherol, and tocopherol esters such as
tocopherol acetates, and the carotenoids includes .beta.-carotene,
canxanthine, astaxanthine and the like.
As actions of dioxabicyclo[3.3.0]octane derivatives, there are known
.DELTA.5-desaturase inhibition, cholesterol uptake inhibition, cholesterol
synthesis inhibition, cholesterol metabolism control, prevention or
treatment of fatty liver, liver disorders caused by alcohol, treatment of
liver disorders caused by chemicals, acceleration of alcohol metabolism,
decrease of serum cholesterol or neutral fat, depression of
parasympathetic nervous functions when eating or drinking, depression of
an increase of temperature of face surface when drinking alcohol and
acceleration of returning to normal temperature, and inhibition of breast
cancer.
As actions of sesamin, there are known acceleration of blood clotting and
hemostatic action, enhancement of insecticidal activity, psychotropically
effective action and the like. Moreover, it is known that sesamolin
exhibits acceleration of blood clotting and hemostatic action.
It is know that sesaminol and stereoisomers thereof, sesamobinol (2-(3,4
-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyelo[3.3
.0]octone), 2-( 3,4-methylenedioxyphenyl)-6-(3-methoxy-4
-hydroxyphenyl)-3,4-dioxabicyclo[3.3.0]octane, pinoresinol
(2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane have
antioxidant activity.
As described above, although dioxabicyclo[3.3.0]octane derivatives have
various actions, the trend of actions is as follows: control of in-vivo
fatty acid metabolism, increase of dihomo-.gamma.-linolenic acid and
eicosanoid thereof, repression of inflammation and thrombus, lowering of
blood pressure, improvement of liver function, inhibition of oncogenesis
of colon cancer and breast cancer, prevention of sick from drink,
alleviation of alcoholism, acceleration of blood clotting, prevention and
treatment of cardiovascular diseases caused by high blood cholesterol, and
prevention of accumulation of cholesterol in various parts of the circular
system; and in case of those having antioxidant action, prevention of
oxidation of oil or fat per se foods containing oil or fat and cosmetics,
inhibition of active oxygen radical formed by peroxidation of cytoplasmic
lipid and cellular components or by metabolism to prevent cell injury.
According to the present invention, the above-mentioned actions are
enhanced by combination with antioxidant such as tocopherol, and a smaller
amount of the dioxabicyclo[3.3.0]octane derivative provides significant
activities.
According to the present invention, although a ratio of
dioxabicyclo[3.3.0]octane and antioxidant is not critical, particularly
for an enhancing of the dioxabicyclo[3.3.0]octane derivatives actions,
especially the cholesterol-lowering action, the ratio of
dioxabicyclo[3.3.0]octane/antioxidant is preferably between 0.001 and
1000, more preferably 0.01 to 20, more preferably 0.1 to 20, most
preferably 0.2 to 10.
The present compositions are provided as pharmaceutical compositions,
cosmetic, food or drinks, or food additives. The pharmaceutical
compositions may be administered exterally, or parenterally, for example,
intramuscularly, subcutaneously, or intravenously.
The dosage varies depending on the purpose of the administration and the
conditions of subjects receiving the composition, but to lower the
cholesterol level, a dose for an oral administration is generally 1 to 100
mg/day, and a dose for a parenteral administration is 0.1 to 20 mg/day,
for an adult human. To prepare an injectable composition, a medical
solubilizing agent such as nonionic surfactant can be used.
More particularly, the present pharmaceutical composition can be prepared,
for example, by dissolving a compound of the present invention in 80
volume of POE(60)-hardened castor oil, or nonionic surfactant such as POE
sorbitan mono oleate with heating, and diluting the resulting mixture with
a physiological saline. Optionally, an isotonic agent, stabilizer, a
preservative, an analgesic and the like may be added. Moreover, if
necessary, emulsions capsules, powders, granules, tablets and the like may
be prepared.
The present invention further provides food additives comprising
dioxabicyclo[3.3.0]octane derivatives and antioxidant. The addition of the
additive is useful because most foods do not contain the same or contain
only a very little amount thereof.
The present invention still further relates to food or drink to which
dioxabicyclo[3.3.0]octane derivatives and/or an antioxidant is added.
Since most food and drink does not contain, or contains in only a very
small amount, both of the above ingredients, then the present food or
drink can be produced by adding both ingredients to such a food or drink.
Nevertheless, some food already contains a sufficient amount of
dioxabicyclo[3.3.0]octane derivative, such as sesamin, and thus it is
sufficient to add only an antioxidant for the production of the present
food and drink. Since dioxabicyclo[3.3.0]octane derivatives, which are
active ingredients of the present compositions, are compounds or analogues
thereof found in conventional food, they are advantageous from a safety
point of view. Moreover, if antioxidants, able to enhance the actions of
dioxabicyclo[3.3.0]octane derivatives are selected from those
conventionally used as antioxidants, they are harmless and have no effect
on the taste of the food or drink.
The food of the present invention, and food to which the present food
additives are added is not limited, but considering the cholesterol
level-lowering action, food containing fat or oil may be considered.
For example, there may be mentioned natural food containing fat or oil,
such as meat, fish, nuts and the like; food to which fat or oil is added
during the cooking thereof, such as Chinese food, Chinese noodle, soup and
the like; food cooked using fat or oil as a heating medium, such as
Japanese Tempura, fried food, Chinese fried rice, doughnuts, sugar-coated
fries and the like; fatty food such as butter, margarine, mayonnaise,
salad dressing, chocolate, instant noodles, caramel, biscuits, ice cream
and the like; and food sprayed or coated with a fat or oil at finish, etc.
Since the addition of the present composition to oil or fat is easy, the
present composition is preferably added to fat or oil. Nevertheless, the
food to which the present composition is added is not limited, and the
present composition may be added to any food to thereby enhance the
dioxabicyclo[3.3.0]octane derivative action of such food.
For food containing the present composition, although the amounts of
dioxabicyclo[3.3.0]octane derivative and antioxidant are not critical, the
dioxabicyclo[3.3.0]octane derivatives are preferably used alone or as a
mixture in an amount of at least 0.0001% by weight, more preferably at
least 0,001% by weight in total, on the basis of the weight of the food;
and antioxidants are preferably added alone or as a mixture in an amount
of at least 0.00001% by weight, more preferably at least 0.0001% by weight
in total, on the basis of the weight of the food. Where an extract
containing dioxabicyclo[3.3.0]octane derivatives is used, the extract is
preferably used in an amount of at least 0.0004% by weight, more
preferably at least 0.004% by weight, on the basis of the weight of the
food.
Since dioxabicyclo[3.3.0]octane derivatives, an active ingredient of the
present composition, are compounds present in conventional food or
analogues thereof, then the food containing dioxabicyclo[3.3.0]octane
derivatives potentially should have the activities of
dioxabicyclo[3.3.0]octane derivatives. In actuality, however, the food
does not sufficiently exhibit the actions of dioxabicyclo[3.3.0]octane
derivatives, because the content thereof is too low.
Accordingly, in one embodiment of the present invention, an antioxidant of
the present invention is added to a food containing
dioxabicyclo[3.3.0]octane derivative in an amount of 0.001 to 1000 parts
by weight, preferably 0.01 to 20 parts by weight, more preferably 0.1 to
20 parts by weight, most preferably 0.2 to 10 parts by weight, relative to
one part by weight of dioxabicyclo[3.3.0]octane derivative contained
therein, to enhance the actions of dioxabicyclo[3.3.0]octane derivatives,
especially the cholesterol level lowering action.
Where food or drink containing dioxabicyclo[3.3.0]octane derivative also
contains an antioxidant, which enhances the actions of the
dioxabicyclo[3.3.0]octane derivative, the same or a different antioxidant
can be further added to the food or drink in a total amount of up to 1000
parts by weight, preferably up to 100 parts by weight, more preferably up
to 20 parts by weight, most preferably up to 10 parts by weight, relative
to one part by weight of the dioxabicyclo[3.3.0]octane derivative, to
obtain food or drink having further enhanced actions, such as a
cholesterol level lowering action, of the dioxabicyclo[3.3.0]octane
derivative. Where tocopherol is used as an antioxidant, for example, where
food or drink containing the dioxabicyclo[3.3.0]octane derivative does not
contain an antioxidant, the tocopherol may be added to the food or drink
in an amount of 0.01 to 100 parts by weight, preferably 0.1 to 20 parts by
weight, most preferably 0.2 to 10 parts by weight, relative to one part by
weight dioxabicyclo[3.3.0]octane derivative, to enhance the actions, such
as the cholesterol level lowering action, of the dioxabicyclo[3.3.0]octane
derivative.
As food containing dioxabicyclo[3.3.0]octane derivatives, there can be
mentioned sesame, washed sesame, peeled sesame, roasted sesame, roasted
and peeled sesame, sesame paste, milled sesame, kneaded sesame, sesame
curd, sesame salad oil, roasted sesame oil, sesame powder and the like.
Note, food to which an antioxidant is added is not limited to sesame-based
food, and the present antioxidants may be added to any food containing
dioxabicyclo[3.3.0]octane derivatives to thereby enhance the actions of
the dioxabicyclo[3.3.0]octane derivative.
According to the present invention a combination of a
dioxabicyclo[3.3.1]octane derivative and antioxidant provide a synergistic
action, such as synergistic lowering of cholesterol level.
EXAMPLES
Next, the present invention is further described in the following Examples.
Example 1.
First, 36 male SD rats, 5 weeks old, were prefed with a standard feed
(solid CE-2, Nippon Clea) for one week, and then were divided into 6
groups each consisting of 6 animals. The animals were fed for two weeks
with a cholesterol-enriched feed comprising 20% casein, 10% powdered beef
tallow, 56.75% granule sugar, 4% cellulose, 1% cholesterol, 0.25% cholic
acid, 1% vitamin mixture (AIN-TM) and 7% mineral mixture (TIN-TM), or
experimental feed supplemented with tocopherol acetate and/or sesamin, in
different amounts. The experimental groups were set as follows:
1. Cholesterol feed
2. Cholesterol feed+1.0% tocopherol acetate
3. Cholesterol feed+0.05% sesamin
4. Cholesterol feed+0.05% sesamin+1.0% tocopherol acetate
5. Cholesterol feed+0.2% sesamin
6. Cholesterol feed+0.2% sesamin+1.0% tocopherol acetate
The above-mentioned tocopherol was DL-.alpha.-tocopherol acetate (Nacalai
Tesque), and the above-mentioned "sesamin" means a mixture of sesamin and
episesamin (sesamin 55.2%, episesamin 44.4%, purity 99.6%) prepared
according to a procedure described in Japanese Unexamined Patent
Publication No. 3-27319.
After being fed for 2 weeks, the animals were starved, and blood samples
were taken. The total cholesterol, HDL-cholesterol, triglycenide
phospholipid, GOT and GPT levels in the sera were measured using a
biochemical automatic analyzer (Hikachi Model 7050). The LDL-cholesterol
value was obtained by calculation. The results are shown in Table 1.
TABLE 1
__________________________________________________________________________
Cholesterol
Cholesterol
Cholesterol
Cholesterol
Cholesterol
Cholesterol
feed +
feed +
feed + feed +
feed +
feed 1.0% V.E.
0.05% SES.
0.05% SES. + V.E.
0.2% SES.
0.2% SES. + V.E.
__________________________________________________________________________
TC (mg/dl)
490 .+-. 229
460 .+-. 172
437 .+-. 187
244 .+-. 57*
371 .+-. 68
.sup..star-solid..star-solid..s
tar-solid. 149 .+-. 21*
(%) 100 94 89 50 76 30
LDL-C (mg/dl)
456 .+-. 221
421 .+-. 174
405 .+-. 181
.sup..star-solid. 213 .+-. 55*
346 .+-. 71
.sup..star-solid..star-solid..s
tar-solid. 109 .+-. 19*
(%) 100 92 89 47 76 24
HDL-C (mg/dl)
17.8 .+-. 8.4
9.9 .+-. 0.9
10.5 .+-. 3.0
13.1 .+-. 2.4
10.3 .+-. 3.0
.sup..star-solid..star-solid..s
tar-solid. 24.2 .+-. 5.7
(%) 100 56 59 74 58 136
LDL-C/HDL-C
26 43 39 16 34 4.5
PL (mg/dl)
176 .+-. 52
186 .+-. 39
168 .+-. 43
126 .+-. 23
150 .+-. 18
.sup..star-solid..star-solid.
122 .+-. 25*
TG (mg/dl)
79 .+-. 32
135 .+-. 49*
91 .+-. 28
90 .+-. 44
71 .+-. 23
71 .+-. 24
GOT (IU/l)
129 .+-. 11
172 .+-. 66
157 .+-. 34
124 .+-. 8
120 .+-. 16
119 .+-. 18
GPT (IU/l)
27 .+-. 3
65 .+-. 48
37 .+-. 10
27 .+-. 3 24 .+-. 2
.sup..star-solid. 34 .+-. 8
__________________________________________________________________________
.
TC: Total cholesterol
LDLC: LDLcholesterol
HDLC: HDLcholesterol
LDL/HDLC: sclerosis factor
TG: Triglyceride
PL: phospholipid
SES: sesamin
V.E.: tocopherol acetate
LDLC = TC(TG/5 + HDLC)
Significant defference to cholesterol feed
*P < 0.05
**P < 0.01
***P < 0.001
Significant defference to cholesterol feed and 0.2% sesamin
.sup..star-solid. < 0.05
.sup..star-solid..star-solid. < 0.01
.sup..star-solid..star-solid..star-solid. < 0.001
An increase of total serum cholesterol value provided by the cholesterol
feed was inhibited in a dose-dependent manner, and the inhibition was
remarkably enhanced by the addition of tocopherol. In the animal group to
which tocopherol alone was provided, the total serum cholesterol level was
not significantly changed, revealing that tocopherol enhances the action
of sesamin in lowering the cholesterol level.
Example 2.
First, 27 SD rats, 5 seeks old, were prefed with a standard feed (solid
CE-2, Nippon Clea) for one week, and then were divided into 4 groups
consisting of 6 or 9 animals. According to a similar procedure as
described in Example 1, the animals were fed with a cholesterol feed, or
with a cholesterol feed supplemented with tocopherol acetate and/or
sesamin, for 2 weeks. The experimental groups were as follows:
1. Cholesterol feed
2. Cholesterol feed+0.2% sesamin
3. Cholesterol feed+0.2% sesamin+0.2% tocopherol acetate
4. Cholesterol feed+0.2% sesamin+1.0% tocopherol acetate
The above-mentioned tocopherol and sesamin were the same as described in
Example 1. After being fed for 2 weeks, the animals were starved for 17
hours, and then blood samples were taken. The total cholesterol,
HDL-cholesterol, triglyceride, phospholipid, GOT, and GPT levels in the
serum were measured using an automatic biochemical analyzer. The
LDL-cholesterol value was calculated. The results are shown in Table 2.
TABLE 2
__________________________________________________________________________
Cholesterol
Cholesterol
Cholesterol
feed + feed +
feed +
0.2% SES. +
0.2% SES. +
Cholesterol feed
0.2% SES.
0.2% V.E.
1.0% V.E.
N = 9 N = 6 N = 6 N = 6
__________________________________________________________________________
Total cholesterol
492 .+-. 66
374 .+-. 157
243 .+-. 11***
184 .+-. 32***
(TC) (mg/dl)
100 76 49 37
(%)
LDL-cholesterol.sup.(1)
471 .+-. 65
349 .+-. 156***
217 .+-. 12***
154 .+-. 29***
(LDL-C) (mg/dl)
100 74 46 33
(%)
HDL-cholesterol
7.3 .+-. 1.7
10.0 .+-. 2.6*
12.8 .+-. 4.3*
17.7 .+-. 2.8***
(HDL-C) (mg/ld)
100 137 175 242
(%) 64.5 34.9
17.0 8.7
LDL-C/HDL-C.sup.(2)
Phospholipid
185 .+-. 32
161 .+-. 41
137 .+-. 18**
121 .+-. 12***
(PL) (mg/dl)
Triglyceride
67.0 .+-. 25.2
71.6 .+-. 27.4
64.4 .+-. 21.5
63.4 .+-. 34.0
(TG) (mg/dl)
GOT (IU/l)
152 .+-. 28
147 .+-. 29
155 .+-. 17
142 .+-. 18
GPT (IU/l)
39 .+-. 8
34 .+-. 6
41 .+-. 9
34 .+-. 5
__________________________________________________________________________
.sup.(1) LDLC = TC(TG/5 + HDLC)
.sup.(2) LDLC/HDL-C: sclerosis index
SES: sesamin
V.E.: tocopherol acetate
Significant difference to cholesterol feed
*P < 0.05
**P < 0.01
***P < 0.001
It was found that tocopherol enhanced the actions of sesamin in a
dose-dependent manner, thus revealing the usefulness of the present
composition.
Example 3.
Sesaminol (Compound A) prepared from purified sesame oil according to
Japanese Unexamined Patent Publication No. 1-243992,
2-(3,4-methylenedioxyphenyl)-6-(3
-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane (Compound C)
prepared by extracting sesame seeds with acetone,
2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane
(Compound D), or
2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyc
lo[3.3.0]octane (Compound E) were used in the following experiments.
First, 42 SD rats, 5 weeks old, were prefed with a standard feed (solid
E-2, Nippon Clea), and were then divided into 7 groups each consisting of
6 animals. Next, the animals were fed with the cholesterol feed as
described in Example 1, or an experimental feed supplemented with
tocopherol acetate and/or Compound A, B, C, D or E, for 2 weeks. The
experimental groups were as follows:
1. Cholesterol feed
2. Cholesterol feed+0.2% sesamin
3. Cholesterol feed+0.2% Compound A+1.0% tocopherol acetate
4. Cholesterol feed+0.2% Compound B+1.0% tocopherol acetate
5. Cholesterol feed+0.2% Compound C+1.0% tocopherol acetate
6. Cholesterol feed+0.2% Compound D+1.0% tocopherol acetate
7. Cholesterol feed+0.2% Compound E+1.0% tocopherol acetate
The above-mentioned tocopherol acetate was the same as used in Example 1.
After being fed two weeks, the animals were starved for 17 hours, and then
blood samples were taken. The total cholesterol level was measured using
an automatic biochemical analyzer, and as a result, it was confirmed that
the up-take of tocopherol acetate significantly enhances the action of
each compound in lowering the cholesterol level. Although the total
cholesterol value in the serum of the first group was increased to
419.+-.153 mg/dl by the cholesterol feed, the administration of sesamin to
the second group reduced the cholesterol value to 361.+-.128 mg/dl. For
the groups 3, 4, 5, 6 and 7, wherein Compounds A, B, C, D and E with
tocophenol acetate were additionally administered, the total cholesterol
values were 198.+-.33, 204.+-.42, 186.+-.37, 211.+-.61 and 218.+-.57 mg/dl
respectively, revealing that the Compound A, B, C, D or E used in
combination with tocophenol further inhibited the increase of the total
cholesterol level value.
Example 4.
First, 100 g of butter fat prepared by eliminating butter milk during the
production of butter by the stirring operation (churning) was mixed with
1.2 g of a mixture of sesamin and episesamin used in Example 1 and 1.2 g
of tocopherol acetate, and the kneading operation (working) was carried
out to obtain a homoqeneous cholesterol level lowering butter containing
the present composition.
Formulation Example 1.
First, 0.25 g of sesamin and 0.25 g of tocopherol acetate were mixed with
20.5 g of silicic anhydride, and 79 g of corn starch was added thereto,
followed by a further mixing. Then to the mixture was added 100 ml of 10%
hydroxypropylcellulose ethanol solution, the mixture was kneaded and
extruded, and the resulting granules were dried.
Formulation Example 2.
First, 3.5 g of sesamin and 0.5 g of tocopherol acetate were mixed with 20
g of silicic anhydride, and to the mixture were then added 10 g of
microcrystalline cellulose, 3.0 g of magnesium stearate, and 60 g of
lactose. The mixture was pressed to form tablet having a diameter of 7 mm
and a weight of 100 mg by using a single-shot tableting machine.
Formulation Example 3.
First, 1.25 g of sesamin and 1.25 g tocopherol acetate were dissolved in
200 g of a nonionic surface active agent TO-1014 (Nikko Chemicals) while
heating at 122.degree. C., and 4.7975 l of sterilized physiological saline
was added thereto. The mixture was then thoroughly stirred, aseptically
filled in vials, which were then closed, to obtain an injectable
formulation.
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